Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence

Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16INK4a, which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence. Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16INK4a, which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence. The Rb (retinoblastoma) family controls cell proliferation by providing a barrier for cell cycle transitions (1Cobrinik D. Oncogene. 2005; 24: 2796-2809Crossref PubMed Scopus (495) Google Scholar). In molecular terms, this barrier consists of repression of the E2F family of transcription factors, which control the synthesis of genes required for cell cycle progression (2Muller H. Bracken A.P. Vernell R. Moroni M.C. Christians F. Grassilli E. Prosperini E. Vigo E. Oliner J.D. Helin K. Genes Dev. 2001; 15: 267-285Crossref PubMed Scopus (633) Google Scholar). Growth factors activate the cyclin-dependent protein kinase (CDK) 2The abbreviations used are: CDK, cyclin-dependent protein kinase; ca-STAT5A, constitutively active STAT5A; HDFs, human diploid fibroblasts; PML, promyelocytic leukemia; PIPES, 1,4-piperazinediethanesulfonic acid. -cyclin complexes that phosphorylate Rb, inhibiting its binding to E2F factors (1Cobrinik D. Oncogene. 2005; 24: 2796-2809Crossref PubMed Scopus (495) Google Scholar). Gain-of-function mutations in genes that stimulate cell cycle progression can potentially disable the Rb barrier, leading to tumorigenesis. Hence, for efficient tumor suppression, normal cells must avoid Rb inactivation by oncogenes. Studies on the senescent cell cycle arrest in response to oncogenic ras have provided a general model of Rb activation by oncogenes in normal cells. Aberrant ras activity induces the expression of CDK inhibitors of the INK4 family such as p15INK4b (3Malumbres M. Perez De Castro I. Hernandez M.I. Jimenez M. Corral T. Pellicer A. Mol. Cell. Biol. 2000; 20: 2915-2925Crossref PubMed Scopus (153) Google Scholar) and p16INK4a (4Serrano M. Lin A.W. McCurrach M.E. Beach D. Lowe S.W. Cell. 1997; 88: 593-602Abstract Full Text Full Text PDF PubMed Scopus (3994) Google Scholar). As a consequence, Rb accumulates in its active hypophosphorylated form during Ras-induced senescence. This pathway is critical for Ras-induced senescence because disabling either p16INK4a or the Rb family inhibits the process (4Serrano M. Lin A.W. McCurrach M.E. Beach D. Lowe S.W. Cell. 1997; 88: 593-602Abstract Full Text Full Text PDF PubMed Scopus (3994) Google Scholar, 5Huot T.J. Rowe J. Harland M. Drayton S. Brookes S. Gooptu C. Purkis P. Fried M. Bataille V. Hara E. Newton-Bishop J. Peters G. Mol. Cell. Biol. 2002; 22: 8135-8143Crossref PubMed Scopus (99) Google Scholar). It is not clear whether the INK4 proteins are universal mediators of Rb activation in response to oncogenic signaling or whether other molecular mechanisms can engage Rb to regulate senescence. To answer this question, we have developed a senescence model in normal human fibroblasts by expressing ca-STAT5A, a constitutively active allele of STAT5A (6Mallette F.A. Gaumont-Leclerc M.-F. Ferbeyre G. Genes Dev. 2007; 21: 43-48Crossref PubMed Scopus (333) Google Scholar). This allele was shown to be constitutively phosphorylated at tyrosine residues, localized to the nucleus, and transcriptionally active (7Onishi M. Nosaka T. Misawa K. Mui A.L. Gorman D. McMahon M. Miyajima A. Kitamura T. Mol. Cell. Biol. 1998; 18: 3871-3879Crossref PubMed Scopus (349) Google Scholar). Hence, ca-STAT5A provides a persistent and unregulated STAT5A signal similar to that observed in some human tumors (8Li H. Ahonen T.J. Alanen K. Xie J. LeBaron M.J. Pretlow T.G. Ealley E.L. Zhang Y. Nurmi M. Singh B. Martikainen P.M. Nevalainen M.T. Cancer Res. 2004; 64: 4774-4782Crossref PubMed Scopus (143) Google Scholar, 9Xi S. Zhang Q. Dyer K.F. Lerner E.C. Smithgall T.E. Gooding W.E. Kamens J. Grandis J.R. J. Biol. Chem. 2003; 278: 31574-31583Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). We show here that ca-STAT5A engages the Rb pathway by down-regulating Myc instead of the p16INK4a-mediated mechanism described in RasV12-induced senescence. As a consequence, cells expressing ca-STAT5 have a decrease in the expression of Myc targets such as CDK4 and an increase in the CDK inhibitor p15INK4b. In agreement, ca-STAT5A-induced senescence is blocked when CDK4 or Myc is overexpressed in combination with dominant-negative p53 or the E6 protein of human papillomavirus. We conclude that the pathways regulating Rb by oncogenic signals are oncogene-specific and discuss the relevance of this concept for human cancers. Cells and Retroviruses—Normal human diploid fibroblasts (HDFs), BJ cells (obtained from Dr. S. W. Lowe), and IMR90 cells (American Type Culture Collection) were cultured in Dulbecco's modified Eagle's medium (Invitrogen) supplemented with 10% fetal bovine serum (HyClone, Logan, Utah) and 1% penicillin G/streptomycin sulfate (Invitrogen). Primary human mammary epithelial cells were cultured in MEGM® (Clonetics) containing 10 ng/ml human epidermal growth factor, 5 μg/ml insulin, 0.5 μg/ml hydrocortisone, 50 μg/ml gentamicin, 50 ng/ml amphotericin B, and 52 μg/ml bovine pituitary extract at 37 °C with 5% CO2. Retroviral vectors are described under supplemental “Experimental Procedures.” Retrovirus-mediated gene transfer, cell proliferation analysis (growth curves and bromodeoxyuridine and [3H]thymidine incorporation assays), cell cycle analysis, and senescence assays were done as described (6Mallette F.A. Gaumont-Leclerc M.-F. Ferbeyre G. Genes Dev. 2007; 21: 43-48Crossref PubMed Scopus (333) Google Scholar, 10Ferbeyre G. de Stanchina E. Querido E. Baptiste N. Prives C. Lowe S.W. Genes Dev. 2000; 14: 2015-2027Crossref PubMed Google Scholar). Protein Expression Analysis—To prepare total cellular protein, cells were collected by trypsinization, washed with phosphate-buffered saline, lysed in 100 μl of SDS sample buffer (60 mm Tris-HCl (pH 6.8), 10% glycerol, 2% SDS, and 5% 2-mercaptoethanol), and boiled for 5 min. For Western blotting, 20 μg of total cellular protein was separated by SDS-PAGE and transferred to Immobilon-P membranes (Millipore Corp.). The primary antibodies used are described under supplemental “Experimental Procedures.” Signals were revealed after incubation with anti-mouse or anti-rabbit secondary antibody coupled to peroxidase (Amersham Biosciences) by enhanced chemiluminescence (ECL, Amersham Biosciences) or Lumi-LightPLUS (Roche Applied Science). Fluorescence microscopy was done as described previously (11Mallette F.A. Goumard S. Gaumont-Leclerc M.-F. Moiseeva O. Ferbeyre G. Oncogene. 2004; 23: 91-99Crossref PubMed Scopus (76) Google Scholar) and is also detailed under supplemental “Experimental Procedures.” To visualize Myc in promyelocytic leukemia (PML) bodies, the protocol was modified by extracting the cells with cytoskeletal buffer (10 mm PIPES (pH 6.8), 100 mm NaCl, 300 mm sucrose, and 3 mm MgCl2) containing 0.5% Triton X-100. Cells were then fixed and treated for immunofluorescence as described (11Mallette F.A. Goumard S. Gaumont-Leclerc M.-F. Moiseeva O. Ferbeyre G. Oncogene. 2004; 23: 91-99Crossref PubMed Scopus (76) Google Scholar). Luciferase Assays—H1299 cells were seeded at 2.5 × 105 cells/well in 6-well plates. Cells were transfected using Lipofectamine 2000 (Invitrogen) with 2 μg of firefly luciferase reporter plasmid under the control of the CDK4 (provided by C. V. Dang, The Johns Hopkins University, Baltimore), p21, or MDM2 promoter; 0.5 μg of Renilla luciferase reporter plasmid under the control of the β-globin promoter; 250 ng of Myc- or p53-expressing plasmid; and increasing amounts (0, 0.1, or 1 μg) of pBabeSTAT5A1*6 (ca-STAT5A). The total quantity of plasmid was kept constant by adding the empty vector pBabe. Cells were harvested 24 h after transfection and processed for Dual-Luciferase assay (Promega) according to the manufacturer's instructions. RNA Analysis—For real-time reverse transcription-PCR or semiquantitative reverse transcription-PCR, 2–5 μg of total RNA was reverse-transcribed with a RevertAid™ H minus first strand synthesis kit (Fermentas Life Sciences) using oligo(dT) primers, and the resulting first strand cDNA was used as a template for PCR. Specific primers are described under supplemental “Experimental Procedures.” ca-STAT5A Induces Senescence in Human Cells—We reported that the DNA damage response (DDR) is required to induce p53 during STAT5-induced senescence (6Mallette F.A. Gaumont-Leclerc M.-F. Ferbeyre G. Genes Dev. 2007; 21: 43-48Crossref PubMed Scopus (333) Google Scholar). However, the mechanism of activation of the Rb pathway in response to ca-STAT5A remained unknown. To investigate how STAT5A engages the Rb pathway, we used a retrovirus that directs the expression of ca-STAT5A in HDFs. As a control, we infected cells with a virus expressing RasV12, which is known to activate Rb by inducing p16INK4a. RasV12- or ca-STAT5A-expressing HDFs proliferated normally during the first 4 days after retroviral infection, indicating that the immediate effect of the introduction of these oncogenes does not inhibit cell growth. However, both RasV12- and ca-STAT5A-expressing cells dramatically decreased their DNA synthesis 8 days after retroviral infection (6 days post-selection) (Fig. 1A) and remained in a non-dividing state for at least 20 days. Cells expressing ca-STAT5A arrested their proliferation with a prominent G1 DNA content (Fig. 1B) and displayed the morphology of flat cells that stained positive for senescence-associated β-galactosidase (Fig. 1A and supplemental Fig. 1A). Notably, the levels of phospho-STAT5A displayed by ca-STAT5A-infected fibroblasts were comparable with those found in the leukemia cell line K562 (Fig. 1C). Next, we used a wild-type allele of STAT5A to investigate if the ability to induce senescence requires tyrosine phosphorylation of STAT5. We found that STAT5A-induced senescence was observed only with the allele STAT5A1*6 and not with wild-type STAT5A (Fig. 1D). Also, ca-STAT5B (known as STAT5B1*6), which has the same activating mutations as STAT5A1*6 but is not constitutively phosphorylated to the same extent (Fig. 1C), was not able to induce senescence in a significant proportion of the cells (data not shown). Hence, as reported for oncogenic ras (12Sarkisian C.J. Keister B.A. Stairs D.B. Boxer R.B. Moody Biol. 2007; PubMed Scopus Google the senescence on the of The senescence response to STAT5A was also in BJ of normal human fibroblasts Fig. and in primary mammary epithelial cells (Fig. Hence, STAT5A-induced senescence is not to IMR90 fibroblasts and in mammary epithelial a cell in which a in both normal H. F. B. J. PubMed Scopus Google Scholar, A. Genes Dev. 1997; PubMed Scopus Google Scholar, I. J. Cell. PubMed Scopus Google Scholar) and I. J. Cell. PubMed Scopus Google Scholar, S. M. Oncogene. 2002; 21: PubMed Scopus (99) Google Scholar, I. S. Zhang Y. E. Singh B. 2004; PubMed Scopus Google Scholar). We that ca-STAT5A senescence in normal cells when to the same extent as found in human providing a model to investigate the mechanisms of Rb activation during oncogene-induced senescence. ca-STAT5A Induces the of CDK4 and the of the Rb in Human activation of the Rb pathway in response to oncogenes in normal cells is known to of CDK inhibitors such as p21, p16INK4a, and p15INK4b S.W. E. G. 2004; PubMed Scopus Google Scholar). To the mechanism of Rb activation during ca-STAT5A-induced we the levels of the and of the Rb pathway (Fig. To senescence by ca-STAT5A was by Rb down-regulation of the genes and and of The was shown to be by Rb, the flat morphology of senescent cells Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and in to Ras-induced ca-STAT5A did not induce p16INK4a or p21 but led to a down-regulation of CDK4 down-regulation was also observed at the (Fig. In consequence, oncogenic STAT5A engages the Rb pathway by a mechanism from the reported during Ras-induced senescence. Next, we whether the observed in CDK4 levels is for STAT5-induced senescence. To the we first IMR90 cells expressing human E6 to the p53 This was because in IMR90 fibroblasts is not to or STAT5-induced senescence by inactivation of the p53 or Rb pathway Fig. As expression of E6 the p53 or CDK4 the Rb did not ca-STAT5A-induced senescence. However, E6 and CDK4 blocked senescence (Fig. of CDK4 during STAT5-induced decrease in CDK4 protein and levels during STAT5-induced senescence either a decrease in CDK4 gene expression or an increase in We first the of STAT5A on the CDK4 and its known H. C. M. Q. W. F. D. B. S. A. 2000; PubMed Scopus Google Scholar). The CDK4 and as reported previously H. C. M. Q. W. F. D. B. S. A. 2000; PubMed Scopus Google is by Myc in transfection assays (data not shown). of ca-STAT5A with Myc and the CDK4 blocked Myc activity in human tumor cells (Fig. However, did not the ability of p53 to stimulate the p21 and MDM2 (Fig. Hence, ca-STAT5A can inhibit Myc are known in the CDK4 these results that ca-STAT5A can general Myc To this we other Myc genes during STAT5-induced senescence. We found a down-regulation of Myc targets such as and (Fig. K. Cancer Res. PubMed Scopus Google Scholar). The of the decrease was similar to the decrease of the E2F We also observed an increase in the gene p15INK4b P. K. A. J. J. H. T. J. J. F. M. Biol. 2001; PubMed Scopus Google Scholar). This CDK inhibitor activate Rb by inhibiting and the levels of CDK4 in cells expressing indicate that a down-regulation of Myc can engage the Rb pathway down-regulation of CDK4 and of p15INK4b from of Myc during STAT5A-induced we Myc levels and activity in the of ca-STAT5A-induced senescence. STAT5-induced senescence a of Myc protein levels (Fig. with the inhibitor Myc levels in the of cell as by immunofluorescence (Fig. This that proteasome-dependent was part of the mechanism of Myc Next, we for genes that Myc by the We first on PML, which is known to be by transcription factors and to in its C. A. M. J. B. P. F. A. Oncogene. Google Scholar). Also, with Myc and induces its M. R. C. I. P. J. Cell. 2004; PubMed Scopus Google Scholar, S. De F. M. P. G. Oncogene. 2005; 24: PubMed Scopus Google Scholar, M. I. A. A. S. S. Oncogene. 2007; PubMed Scopus Google Scholar). As we found that ca-STAT5A the of when in normal human fibroblasts (Fig. Also, using we revealed that a of these with Myc during STAT5-induced senescence (Fig. the extent of was was similar to of Myc localization to M. R. C. I. P. J. Cell. 2004; PubMed Scopus Google Scholar, S. De F. M. P. G. Oncogene. 2005; 24: PubMed Scopus Google Scholar). the are with a model of localization of Myc to bodies, Myc that to the These results with that STAT5A is required to induce Myc in cells treated with J.D. J. 2000; PubMed Scopus Google Scholar). We that the down-regulation of Myc we observed in STAT5A-induced senescence is not an immediate and of normal signaling but the of a cellular response to and unregulated Myc with E6 to STAT5-induced investigate whether the down-regulation of Myc by ca-STAT5A is to the of senescence the Rb pathway, we HDFs in which the p53 pathway was using In this we can the of the pathway in Introduction of ca-STAT5A in HDFs senescence as described (Fig. However, of ca-STAT5A with Myc and E6 dramatically the of senescent cells (Fig. allele of Myc with to the R. F. E. Y. K. J.R. Genes Dev. 2000; 14: PubMed Scopus Google Scholar) was in STAT5A-induced senescence. Myc and were also able to CDK4 expression in cells (Fig. the mechanism by ca-STAT5A also the of the Myc from a retroviral the levels of Myc were in control cells (Fig. These results indicate that Myc is able to the Myc of cells expressing We here a novel mechanism of activation of the Rb pathway in response to oncogenic allele of STAT5A that the activation of in human tumors the Rb pathway by Myc expression and STAT5A-induced at least Myc targets were as mediators of Rb activation in response to Myc the levels of the CDK4 protein kinase were but the levels of the gene a CDK were These mechanisms can to Rb E2F which is required for cell cycle This Myc activity is for STAT5A senescence because the process was by expression of Myc or CDK4 in cells in which p53 was by In with has reported that of expression can to cellular senescence in both normal and tumor cells I. S. S. A. PubMed Scopus Google Scholar, J. A. P. S. A. 2007; PubMed Scopus Google Scholar). an pathway of repression that the oncogenic provided by activation of model to STAT5A-induced senescence tumor pathways that can to the ca-STAT5A can induce senescence in cells in which either the Rb or p53 pathway is but not in cells in which both pathways are (Fig. These of the Rb and p53 pathways to regulate senescence in tumor cell when p53 or Rb is inactivated. It is not clear if the Rb and p53 pathways are to oncogenes results have that p53 is in response to a of oncogenes the DNA damage response (6Mallette F.A. Gaumont-Leclerc M.-F. Ferbeyre G. Genes Dev. 2007; 21: 43-48Crossref PubMed Scopus (333) Google Scholar, J. N. M. P. D. N. E. K. M. H. F. K. F. M. T. J. C. T. J. PubMed Scopus Google Scholar, R. M. A. S. P. C. C. M. A. R. F. PubMed Scopus Google Scholar). STAT5A-induced of expression using RNA does not Rb-dependent senescence (6Mallette F.A. Gaumont-Leclerc M.-F. Ferbeyre G. Genes Dev. 2007; 21: 43-48Crossref PubMed Scopus (333) Google that the of DNA damage signaling does not oncogenes to the Rb However, STAT5-induced DNA damage signal to the Rb pathway mechanisms that in regulating Myc levels (Fig. It is significant that in normal human the expression of Myc that of and CDK4, which are negative of the Rb with this expression of Myc in human primary epithelial cells the Rb pathway, leading to cellular J. P. M. D. Peters G. A. Beach D. Cancer Res. 2005; PubMed Scopus Google Scholar). Also, Myc inactivation in tumor induces tumor cellular senescence. However, inactivation of the Rb pathway this tumor J. A. P. S. A. 2007; PubMed Scopus Google Scholar). It has that Myc on Rb to regulate cell proliferation N. R. PubMed Scopus Google Scholar). 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Full Text Full Text PDF PubMed Scopus Google we did not Myc and CDK4 down-regulation during Ras-induced senescence. other genes a critical in Myc The expression of Myc was to the mechanisms of Myc down-regulation by Myc was not in cells expressing This that the Myc pathway can be or by levels of the of the gene is a oncogenic M. Google Scholar). the other Myc is at and is that ca-STAT5A engage other mechanisms that Myc or RNA levels M. PubMed Scopus Google Scholar, C. H. B. 1998; PubMed Scopus Google Scholar, A. M. M. G. T. V. Mol. Cancer Res. PubMed Scopus Google Scholar, C. N. M. B. P. S. A. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar). STAT5-induced senescence provides a model to the has for tumors that are by activation of STAT5. These such as Y. A. Y. K. M. S. M. Miyajima A. Kitamura T. H. J. 2005; PubMed Scopus Google Scholar, C. F. M. J.D. 2000; PubMed Google Scholar, T. R. J. R. Oncogene. 2000; PubMed Scopus Google Scholar, R. V. C. K. S. A. A. 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